Colorectal cancer (CRC) is one of the most common fatal cancers in developed countries, and the worldwide incidence is increasing. The United States and the United Kingdom are high incidence countries, with an estimated 133,500 new cases and 55,300 deaths (Parker et al. CA Cancer J. Clin. 1996 46:5-27) in the United States and 30,941 cases and approximately 17,000 deaths in the United Kingdom (HMSO UK Cancer Registry Data). The population lifetime risk is 1 in 25 in the United States and Northern Europe and thus represents a significant public health issue (Sharp et al. Cancer Registration Statistics Scotland 1981-1990, Information and Statistics Division, The National Health Service in Scotland, Edinburgh (1993)). Identification of people who are predisposed to the disease would allow targeting of effective preventative measures with the aim of reducing the considerable cancer related mortality (Burke et al. J. Am. Med. Ass'n. 1997 227:915-919).
One group of people with a very high colorectal cancer risk are those who carry germline mutations in genes that participate in DNA mismatch repair. hMSH2 (Fishel et al. Cell 1993 75:1027-1038; Leach et al. Cell 1993 75:1215-1225; U.S. Pat. No. 5,591,826) and hMLH1 (Bronner et al. Nature 1994 368:258-261; Papadopoulos et al. Science 1994 263:1625-1629; PCT Publication No. WO 95/20678, published on Aug. 3, 1995) are the two genes most commonly involved in heredity predisposition to CRC, but mutations in hPMS1 and hPMS2 also occur in a minority of cases (Nicolaides et al. Nature 1994 371:75-80). Such mutations are usually associated with marked familial aggregation of colorectal, uterine and other cancers constituting the clinically defined autosomal dominant syndrome of hereditary non-polyposis colorectal cancer (HNPCC) (Lynch et al. Gastroenterology 1993 104:1535-1549; Liu et al. Nature Med. 1996 2:169-174; Wijnen et al. Am. J. Hum. Genet. 1995 56:1060-1066; Mary et al. Hum. Mol. Genet. 1994 3:2067-2069; Nystrom-Lahti et al. Nature Med. 1995 1:1203-1206). However, an appreciable proportion of patients who have early onset colorectal cancer but who do not fulfill pragmatic criteria for HNPCC (Vasen et al. Dis. Colon Rectum 1991 34:424-425) also carry mismatch repair gene mutations (Liu et al. Nature Med. 1995 2:169-174; Dunlop et al. Br. Med. J. 1997 314:1779-1780). Thus, restricting genetic testing to individuals from families fulfilling HNPCC criteria is likely to exclude a significant fraction of gene carriers in the general population. However, screening unselected patients with sporadic cancer represents an enormous workload and may provide a very low yield of mutation carriers (Liu et al. Nat. Med. 1995 1:348-352; Tomlinson et al. J. Med. Genet. 1997 34:39-42).
It is clear that issues concerning indications for genetic testing and interpretation of results are critical in hereditary cancer syndromes (Giardiello et al. N. Engl. J. Med. 1997 336: 823-827).
Using a population-based approach, factors indicative of the likelihood of identifying patients with mismatch repair gene mutations were investigated. Improved approaches to mutation detection and the prevalence of detectable mismatch repair gene alterations in various screened groups who were not selected on the basis of family history were also determined.